CA-3124986-C - SPHINGOSINE PATHWAY MODULATING COMPOUNDS FOR THE TREATMENT OF CANCERS

Abstract

The invention provides methods and compositions for treating cancers and myeloproliferative disorders using sphingosine kinase-1 inhibitors, such as SK1-I, and selective sphingosine-1-phosphate receptor agonists, such as ozanimod.

Inventors

• Elazar Rabbani
• James J. Donegan
• Paul Diamond

Assignees

• ENZO BIOCHEM, INC.
• Elazar Rabbani
• James J. Donegan
• Paul Diamond

Dates

Publication Date

20260505

Application Date

20181221

Priority Date

20180625

Claims (16)

1. 34 WHAT IS CLAIMED IS: 1. Use of ozanimod or a pharmaceutically acceptable salt thereof in the treatment of a leukemia in a mammalian subject.
2. 2. Use of ozanimod or a pharmaceutically acceptable salt thereof in combination with a compound having the structure or a pharmaceutically acceptable salt thereof in the treatment of a leukemia in a mammalian subject.
3. 3. A pharmaceutical composition for the treatment of a leukemia in a mammalian subject, comprising a therapeutically effective amount of ozanimod or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
4. 4. Use of ozanimod or a pharmaceutically acceptable salt thereof in the treatment of pancreatic cancer in a mammalian subject.
5. 5. Use of ozanimod or a pharmaceutically acceptable salt thereof in combination with a compound having the structure or a pharmaceutically acceptable salt thereof in the treatment of pancreatic cancer in a mammalian subject.
6. 6. A pharmaceutical composition for the treatment of pancreatic cancer in a mammalian subject, comprising a therapeutically effective amount of ozanimod or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
7. 7. Use of ozanimod or a pharmaceutically acceptable salt thereof in the treatment of a cancer in a mammalian subject.
8. 8. The use of claim 7, wherein the cancer is acute lymphoblastic leukemia (ALL).
9. 9. The use of claim 7, wherein the cancer is hepatocellular carcinoma (HCC).
10. 10. Use of ozanimod or a pharmaceutically acceptable salt thereof in the treatment of a myeloproliferative disorder in a mammalian subject.
11. 11. A pharmaceutical composition for the treatment of a cancer or a myeloproliferative disorder in a mammalian subject, comprising: a therapeutically effective amount of ozanimod or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.
12. 12. The pharmaceutical composition of claim 11, further comprising a therapeutically effective amount of a sphingosine kinase type I inhibitor.
13. 13. The pharmaceutical composition of claim 12, wherein the sphingosine kinase type I inhibitor comprises the compound or a pharmaceutically acceptable salt thereof.
14. 14. The pharmaceutical composition of any one of claims 11-13, further comprising a therapeutically effective amount of 6-[(2S,4R,6E)-4-Methyl-2-(methylamino)-3-oxo-6- octenoic acid]cyclosporin D or a pharmaceutically acceptable salt thereof.
15. 15. Use of ozanimod or a pharmaceutically acceptable salt thereof for the induction of apoptosis in mammalian cancer cells.
16. 16. The use of claim 15, for the induction of apoptosis in mammalian hepatocellular carcinoma cells.

Description

1 SPHINGOSINE PATHWAY MODULATING COMPOUNDS FOR THE TREATMENT OF CANCERS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. application serial no. 16/017,303 filed June 25, 2018. FIELD OF THE INVENTION [0002] The invention relates to the field of pharmaceutical treatment of cancers. BACKGROUND [0003] Sphingosine-l -phosphate (S1P) was discovered to be a bioactive signaling molecule over 20 years ago. Studies have since identified two related kinases, sphingosine kinase 1 and 2 (a/k/a sphingosine kinase “type I” and “type II” respectively, and SphK1 and SphK2 respectively), which catalyze the phosphorylation of sphingosine to S1P. Extracellular S1P can bind to and activate each of five S1Pspecific, G protein-coupled receptors (designated SIPR1-5) to regulate cellular and physiological processes in an autocrine or paracrine manner. Selective inhibitors of each of sphingosine kinase 1 and 2, as well as both non- selective and selective agonists of S1PRs, have been developed and are known in the art. SUMMARY [0004] One embodiment of the invention provides a method for treating liver cancer, such as hepatocellular carcinoma (HCC), in a mammalian subject, such as a human, that includes the step of: administering to a mammalian subject in need of treatment for liver cancer, a therapeutically effective amount of a sphingosine kinase type I inhibitor, such as SK1-I or a pharmaceutically acceptable salt thereof. [0005] A related embodiment of the invention provides a pharmaceutical composition that includes a sphingosine kinase type I inhibitor, such as SK1-I or a pharmaceutically acceptable salt thereof for the treatment of liver cancer, such as HCC, in a mammal, such as a human patient. [0006] Another embodiment of the invention provides a method for treating a cancer or a myeloproliferative disorder (myeloproliferative neoplasm) in a mammalian subject, such as a human, that includes the step of: administering to a mammalian subject in need of treatment for a cancer or myeloproliferative disorder, a therapeutically effective amount of a sphingosine-l -phosphate receptor agonist, such as an 2 agonist of one or both of sphingosine-l -phosphate receptor-l (S1P1) and sphingosine-l -phosphate receptor-5 (S1P5) such as ozanimod (RPC1063) or a pharmaceutically acceptable salt thereof, or an active metabolite of ozanimod or a pharmaceutically acceptable salt thereof. [0007] A related embodiment of the invention provides a pharmaceutical composition for the treatment of a cancer or a myeloproliferative disorder (myeloproliferative neoplasm) in a mammalian subject, such as a human, that includes: a therapeutically effective amount of a sphingosine-l -phosphate receptor agonist, such as an agonist of one or both of sphingosine-l -phosphate receptor-l (S1P1) and sphingosine-l -phosphate receptor-5 (S1P5) such as ozanimod (RPC1063) or a pharmaceutically acceptable salt thereof, or an active metabolite of ozanimod or a pharmaceutically acceptable salt thereof. [0008] Still another embodiment of the invention provides a method for treating a cancer or a myleoproliferative disorder (myeloproliferative neoplasm), such as any of those disclosed herein, in a mammalian subject, such as a human, including the step of: co-administering to a mammalian subject in need of treatment for a cancer or myeloproliferative disorder, a therapeutically effective amount of: (a) a sphingosine kinase type I inhibitor, such as one disclosed in U.S. Patent No. 8,372,888 and/or 8,314,151, such as SK1-I, or a pharmaceutically acceptable salt thereof; and (b) one or more immune checkpoint inhibitors, which may be monoclonal antibodies, such as one or more selected from the group consisting of: PD-l inhibitors such as mAbs Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®); PD-L1 inhibitors such as mAbs Atezolizumab (Tecentriq®), Avelumab (Bavencio®), and Durvalumab (Imfinzi®); and CTLA-4 inhibitors such as mAh Ipilimumab (Yervoy®); and V-domain Ig Suppressor of T Cell Activation (VISTA) inhibitors such as mAh JNJ61610588 (ImmuNext Inc.). [0009] Additional features, advantages, and embodiments of the invention may be set forth or apparent from consideration of the following detailed description, drawings if any, and claims. Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS 3 [0010] FIG. 1 shows MTT assay data (72 hours) for various concentrations of ozanimod for four human hepatocellular carcinoma cell lines. [0011] FIG. 2 shows MTT assay data (72 hours) for various concentrations of ABC294640 for four human hepatocellular carcinoma cell lines. [0012] FIG. 3 shows MTT assay data (72 hours) for various concentrations of SK1-I for four human hepatocellular carcinoma cell lines. [0013] FIG. 4 A shows MTT assay